The fatty acid synthasefasn-1acts upstream of WNK and Ste20/GCK-VI kinases to modulate antimicrobial peptide expression inC. elegansepidermis

Abstract

An important part of the innate immune response of the nematode C. elegans to fungal infection is the rapid induction of antimicrobial peptide gene expression. One of these genes, nlp‑29, is expressed at a low level in adults under normal conditions. Its expression is up-regulated in the epidermis by infection with Drechmeria coniospora, but also by physical injury and by osmotic stress. For infection and wounding, the induction is dependent on a p38 MAP kinase cascade, but for osmotic stress, this pathway is not required. To characterize further the pathways that control the expression of nlp‑29, we carried out a genetic screen for negative regulatory genes. We isolated a number of Peni (peptide expression no infection) mutants and cloned one. It corresponds to fasn‑1, the nematode ortholog of vertebrate fatty acid synthase. We show here that a pathway involving fatty acid synthesis and the evolutionary conserved wnk‑1 and gck‑3/Ste20/GCK‑VI kinases modulates nlp‑29 expression in the C. elegans epidermis, independently of p38 MAPK signaling. The control of the antimicrobial peptide gene nlp‑29 thus links different physiological processes, including fatty acid metabolism, osmoregulation, maintenance of epidermal integrity and the innate immune response to infection.

GCN-2 dependent inhibition of protein synthesis activates osmosensitive gene transcription via WNK and Ste20 kinase signaling

“…WNK-1 and GCK-3 control important physiological processes in C. elegans including systemic fluid balance during hypertonic stress (9), cell cycle-and cell volume-dependent activity of the CLC anion channel CLH-3b (13,15), developmental processes (19,26), and hypertonic stress-induced expression of the antimicrobial peptide NLP-29 (29). Our findings together with those of Lee et al (29) define a novel role for WNK and GCK-VI kinases in regulating osmosensitive gene expression.…”

“…Our findings together with those of Lee et al (29) define a novel role for WNK and GCK-VI kinases in regulating osmosensitive gene expression. We suggest that inhibition of mRNA translation activates WNK-1/GCK-3 signaling, which in turn activates gpdh-1 transcription.…”

Quantitative and Automated High-throughput Genome-wide RNAi Screens in <em>C. elegans</em>

“…On the other hand, in dry plates, the osmolarity of the culture medium increases. This has direct effects on worm physiology 17 , including the induction of some antimicrobial peptide genes, such as nlp 29 18 . The volume used to dispense worms and spores is critical to allow effective and rapid drying.…”

From the outside in and the inside out: Antifungal immune responses inCaenorhabditis elegans

“…6 In this issue of Virulence, Lee et al explore the signaling pathways, independent of the p38 MAP kinase cascade, that are involved in the modulation of antimicrobial peptide gene expression in the epidermis. 16 This work defines a role for the fatty acid synthase gene FASN-1 and the evolutionary conserved wnk-1 and gck-3/Ste20/ GCK-VI kinases in the regulation of nlp-29. Taken together with previous work, these experiments underscore the findings that nlp-29 expression is modulated both by infectious and non-infectious stimuli, the latter of which includes fatty acid metabolism and osmoregulation.…”